Alzheimer's disease (AD) is the leading cause of dementia in the elderly and is without a cure. Accumulating pathology, including beta-amyloid (Aß) deposits and tau inclusions, disrupts synaptic plasticity, particularly long-term potentiation (LTP) in cortical regions critical for memory. While animal studies link axon initial segment (AIS) changes to impaired plasticity, this remains unexplored in humans. We use idiopathic normal pressure hydrocephalus (iNPH) brain biopsies and advanced electrophysiology, single nuclei RNA sequencing, and patient neuroimaging (TMS, fMRI) to mechanistically study how AD pathology leads to disruptions in AIS integrity and plasticity. By correlating AIS disruptions with patient imaging and integrating findings with proteomic and genetic data, we aim to identify biomarkers predictive of AD progression. This innovative study bridges molecular and structural changes to functional outcomes, offering new insights into early memory decline mechanisms in AD.

2025

2029